Protease inhibitors

Patent metadata

Field	Value
Publication number	US-9428517-B2
Application number	US-201514940817-A
Country	US
Kind code	B2
Filing date	Nov 13, 2015
Priority date	Sep 24, 2008
Publication date	Aug 30, 2016
Grant date	Aug 30, 2016

Abstract

Compounds of the formula II:

wherein
R 1 and R 2 are independently H, F or CH 3 ; or R 1 forms an ethynyl bond and R 2 is H or C 3 -C 6 cycloalkyl which is optionally substituted with one or two substituents independently selected from methyl, CF 3 , OMe or halo; R 3 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, either of which is optionally substituted with one or two methyl and/or a fluoro, trifluoromethyl or methoxy, when R 3 is C 3 -C 6 cycloalkyl it may alternatively be gem substituted with fluoro; R 4 is methyl or fluoro; m is 0, 1 or 2; E is a bond, or thiazolyl, optionally substituted with methyl or fluoro; A 1 is CH or N, A 2 is CR 6 R7 or NR 6 , provided at least one of A 1 and A 2 comprises N; R 6 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 3 alkyl-O—C 1 -C 3 alkyl, or when A 2 is C, R 6 can also be C 1 -C 4 alkoxy or F; R 7 is H, C 1 -C 4 alkyl or F

or a pharmaceutically acceptable salt, N-oxide or hydrate thereof, have utility in the treatment of disorders characterized by inappropriate expression or activation of cathepsin K, such as osteoporosis, osteoarthritis, rheumatoid arthritis or bone metastases.

First claim

The invention claimed is:

1. A compound of the formula 2a:

2. A process for the preparation of a compound of formula 2b comprising the step of dehydrating a compound of formula 2a as outlined in the scheme:

3. A process for the preparation of a compound of claim 1 comprising
removal of the N-protecting Boc group of the compound of formula
followed by coupling of the acid of the compound of the formula

as outlined in the step below:

4. The process according to claim 3 wherein the compound of formula

is prepared by a process comprising removal of the N-protecting Boc group from a compound of formula 4b, followed by coupling of Boc-Leu-OH as outlined in the scheme:

Assignees

• Medivir Ab

Inventors

• Oden Lourdes Salvador
• Nilsson Magnus
• Kahnberg Pia
• Samuelsson Bertil
• Grabowska Urszula

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P3/14

  for calcium homeostasis (vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04) · CPC title